The purpose of this proposal is to test the hypothesis that renal renin release underlies the pathogenesis of post-ischemic acute renal failure in an experimental model of kidney harvesting, preservation and transplantation. Drugs which interfere with the formation or action of angiotensin will be used to study the pharmacologic means and mechanisms by which post-ischemic acute renal failure can be prevented. In addition, we will specifically extend our reported findings that propranolol is effective in preventing renal ischemic damage. The experimental model to be studied is one in which a canine kidney is subjected to 60 min warm ischemia, placed on hypothermic (8 degrees C pulsatile perfusion preservation and then autotransplanted with an immediate contralateral nephrectomy. In this model only 40% of the untreated kidneys can support life. Our preliminary results show that when d-propranolol (50 mg/liter) or N-dimethyl propranolol (100 mg/liter) is added to the perfusate during preservation after the ischemic insult, survival increased to 87% and 75% respectively. In this proposal, we will investigate the mechanisms by which these and other similar drugs are effective in enhancing the kidney's tolerance to ischemia. We will look at the ability of the angiotensin antagonists, converting enzyme inhibitor, propranolol and itsisomers, other beta-antagonists, and membrane stabilizing compounds to enhance the kidney's tolerance to ischemia. We will look at the ability of the angiotesin antagonists, converting enzyme inhibitor propanolol and its isomers, other beta-antagonists, and membrane stabilizing compounds to enhance the kidney's tolerance to ischemia. We will study the interaction of these drugs with the renin-angiotensin system to see if their protective effect is due to a blockade of the renin-angiotensin system or to another effect such as membrane stabilization. The effect of these compounds on renal hemodynamics and function will also be studied in the rat. With this approach, we will be able to better define the intrinsic characteristics of drugs which can enhance the kidney's ability to withstand ischemia. The ultimate goal is to improve the quality of kidneys which are destined for transplantation.